In past studies, we established that interleukin-1, bacterial lipopolysaccharides and retinoic acid are strong inducers of catabolism in cultured articular cartilage and that in opposing fashion, insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta (TGF-beta) reduce catabolism and increase synthesis of matrix components. We proposed that these effectors are part of a tightly regulated circuitry in cartilage that is flexibly modulated to direct growth, homeostasis, catabolism and/or repair. We have focused on characterizing the accessory proteins/ signaling intermediates to two of the major mediators, interleukin-1 and IGF-1. We established the presence of two binding proteins of IGF-1 in bovine articular cartilage, of approximately 33 and 24 Kda. The first was identified as IGF-BP-2 and the second was tentatively identified as IGF-BP-4, and shown to be synthesized by the chondrocytes. We found that these proteins are present in cartilage throughout its developmental growth and we are now exploring whether these proteins play a pivotal role in directing tissue growth. In collaboration with Dr Chris Evans, we examined the role of nitric oxide in articular cartilage metabolism and found that this gas is 1) induced by interleukin-1 treatment of bovine articular cartilage organ cultures and 2) it protects cartilage from the degradative effects induced by the cytokine. We suggest that nitric oxide is a feedback inhibitor of interleukin-1 action.